Submissions for variant NM_002778.4(PSAP):c.679_681del (p.Lys227del)

gnomAD frequency: 0.00003  dbSNP: rs1431844269

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Experimental Endocrinology, Slovak Academy of Sciences	RCV000755006	SCV000809015	likely pathogenic	Sphingolipid activator protein 1 deficiency	2018-08-01	criteria provided, single submitter	clinical testing	Observed in compound heterozygosity with NM_002778.2:c.1268del.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000755006	SCV002097582	pathogenic	Sphingolipid activator protein 1 deficiency		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755006	SCV002255438	likely pathogenic	Sphingolipid activator protein 1 deficiency	2024-01-24	criteria provided, single submitter	clinical testing	This variant, c.679_681del, results in the deletion of 1 amino acid(s) of the PSAP protein (p.Lys227del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with PSAP-related conditions (PMID: 30632081, 31319425, 32180488). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 562226). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307590	SCV002600466	likely pathogenic	Metachromatic leukodystrophy	2022-10-12	criteria provided, single submitter	clinical testing	Variant summary: PSAP c.679_681delAAG (p.Lys227del) results in an in-frame deletion that is predicted to remove 1 amino acid from the Saposin B type domain in the encoded protein. The variant was absent in 251484 control chromosomes (gnomAD). c.679_681delAAG has been reported in the literature as a biallelic genotype in individuals affected with Metachromatic Leukodystrophy (Kolnikova_2019, Madaan_2019, Parayil Sankaran_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477518	SCV002795564	likely pathogenic	Gaucher disease due to saposin C deficiency; Krabbe disease due to saposin A deficiency; Combined PSAP deficiency; Sphingolipid activator protein 1 deficiency; Parkinson disease 24, autosomal dominant, susceptibility to	2022-04-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420203	SCV004106287	likely pathogenic	PSAP-related disorder	2022-11-09	criteria provided, single submitter	clinical testing	The PSAP c.679_681delAAG variant is predicted to result in an in-frame deletion (p.Lys227del). This variant has been reported in the homozygous and compound heterozygous states in individuals with autosomal recessive metachromatic leukodystrophy due to SAP-b deficiency (Kolnikova et al. 2019. PubMed ID: 30632081; Madaan et al. 2019. PubMed ID: 31319425; Parayil Sankaran et al. 2020. PubMed ID: 32180488). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000755006	SCV005046815	pathogenic	Sphingolipid activator protein 1 deficiency	2024-05-31	criteria provided, single submitter	clinical testing	A homozygous 3 base pair deletion in exon 6 of the PSAP gene. The observed variant c.679_681(p.Lys227del) has not been reported in the 1000 genomes and gnomAD database. The in silico predictions is damaging by MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000755006	SCV005061138	likely pathogenic	Sphingolipid activator protein 1 deficiency		criteria provided, single submitter	clinical testing	The observed inframe deletion variant c.679_681del(p.Lys227del) in PSAP gene has been reported previously reported in homozygous, compound heterozygous state in individuals with Metachromatic Leukodystrophy (Madaan P, et al., 2019, Kolnikova M, et al., 2019). The c.679_681del variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. However, experimental studies on the pathogenicity of the variant are not available. This p.Lys227del causes deletion of amino acid Lysine at position 227. For these reasons, this variant has been classified as Likely Pathogenic.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001528144	SCV001739355	likely pathogenic	Combined PSAP deficiency	2021-05-27	no assertion criteria provided	clinical testing